Alzheimer's disease is a dementia that involves progressive deposition of amyloid β-protein (Aβ) in brain regions important for memory and cognition, followed by secondary inflammation that contributes to the neuropathologic process. Immunization with Aβ can reduce cerebral Aβ burden and consequent neuropathologic changes in the brains of mice transgenic for the β-amyloid precursor protein (APP). We found that transgenic expression of human APP in B6SJL mice, under the prion promoter, results in immune hyporesponsiveness to human Aβ, in terms of both antibody and cellular immune responses. The decreased antibody responses were related not to B cell tolerance but rather to the inability of Aβ-specific T cells to provide help for antibody production. The immune hyporesponsiveness could be overcome if T cell help was provided by coupling an Aβ B cell epitope to BSA. Our results suggest that expression of APP in transgenic mice is associated with an Aβ-specific impaired adaptive immune response that may contribute to the neuropathology. Moreover, humans with life-long elevation of brain and peripheral Aβ (e.g., patients with presenilin mutations or Down syndrome) could have reduced immune responses to Aβ vaccination.